Impact of heme and heme degradation products on acute kidney injury associated with Shiga toxin 2-induced hemolytic-uremic syndrome

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The hemolytic-uremic syndrome (HUS) is a serious extra-intestinal complication of infections with enterohemorrhagic Escherichia coli (EHEC). Bacterial Shiga toxins (Stx), in particular Stx2, play an essential role in HUS pathogenesis by triggering thrombotic microangiopathy and subsequently the typical triad of symptoms of hemolytic anemia, thrombocytopenia and acute kidney injury. Recently, the central role of extracellular "free" heme as a perpetuating factor in lifethreatening infections, even with a very moderate degree of hemolysis, has been acknowledged. However, the impact of hemolysis, "free" heme and heme degradation products (HHDPs) as well as hemoglobin- and heme-neutralizing proteins and heme-catabolizing enzymes (heme oxygenase 1, HO1) on the degree of acute kidney injury in HUS, as a paradigm for hemolytic anemia with concomitant inflammation, requires investigation. In striking contrast to other forms of hemolytic anemia, a parallel decrease in erythropoietin (EPO) serum levels has been described in HUS patients. This might be due to either inflammation via inhibition of EPO gene expression or a HUS characteristic direct damage to the kidneys with concomitant renal anemia. The pleiotropic hormone EPO is known to have organ protective properties, which are independent of its well-established hematopoietic effects. There is increasing evidence that the tissue-protective effects of EPO are mediated by a heterocomplex of the erythropoietin receptor and the b-common receptor (bcR) that is pharmacologically distinct from the erythropoietin receptor homodimer conveying erythropoiesis. Thus, a critical imbalance between hemolysis/heme-dependent injury and EPO/bcR-dependent protection might aggravate renal dysfunction in HUS. Understanding this imbalance carries the potential for novel therapeutic strategies. In the proposed subproject we aim to establish the role of hemolysis/extracellular heme and the EPO/bcR signaling axis in the development of HUS-associated acute kidney injury. In a translational approach we will specifically investigate (i) the role of hemolysis and formation of HHDPs (ii) the impact of hemoglobin- and heme-scavenging proteins (iii) the impact of HO1, and (iv) the impact of EPO and the potential bcR-mediated tissue protective effects of EPO on renal dysfunction and injury in HUS. We will address these objectives systematically in a model of Stx2-mediated experimental HUS by employing mice deficient for haptoglobin, hemopexin, HO1 or bcR. These mechanistic murine studies will be complemented by quantification of HHDPs and EPO in serum samples from HUS patients and by correlating the results to the degree/outcome of renal dysfunction in these patients. The proposed studies will enable us to characterize the impact of hemolysis/heme and the EPO/bcR signaling axis in the pathogenesis of Stx2 propagated renal dysfunction and injury, a significant risk factor for end-stage kidney disease.